MicroRNAs: the Big Impact of Small RNAs on Gene Expression
Amy E. Pasquinelli
Department of Biology, University of California, San Diego
Since the recent emergence of microRNAs (miRNAs) as a new class of regulatory RNAs (ribonucleic acids), rapid progress has been made in identifying new members of this class and in determining factors important for their expression and function. As their name suggests, miRNAs function as tiny ~22 nucleotide RNA molecules that control the expression of protein-coding genes. MiRNAs act in diverse biological pathways in all multicellular organisms. The human genome encodes potentially thousands of distinct miRNAs and mis-regulation of specific miRNA pathways can lead to diseases, including cardiac malfunction and cancer. With so many new regulatory molecules comes the challenge of understanding how they are produced at the right time, in the right place and at appropriate levels. Furthermore, miRNAs serve as guides to control other gene products but we still have much to learn about how miRNAs recognize and regulate specific target genes. The first miRNA genes were discovered as regulators of development in the nematode worm Caenorhabditis elegans. My lab uses this simple animal model to answer the basic questions of how miRNAs are expressed and function in the context of a living organism. Many of the miRNA genes and protein factors involved in their production and function are conserved from worms to humans. Understanding miRNA pathways C. elegans will help elucidate roles for human miRNAs and reveal how mis-regulation of these pathways can contribute to human disease. Finally, the use of small RNAs to control the expression of specific target genes holds immense promise in the biomedical field, but this therapy is dependent on understanding the parameters that mediate recognition between the regulatory RNA and its target and the biological output of such interactions. Thus, deciphering the rules that mediate endogenous miRNA-target interactions has important implications for engineering potent and specific RNA-based drugs.
However, the mechanism by which these regulatory RNAs inhibit the expression of specific target messenger RNAs (mRNAs) is still unclear. My lab primarily focuses on the founding miRNA genes, lin-4 and let-7, and their genetically defined targets in the nematode C. elegans to understand how these miRNAs control development of the animal. The majority of animal miRNAs, including lin-4 and let-7, recognize sites of partial complementarity in the 3' untranslated regions (UTRs) of target genes, and this is believed to result in translational repression. Recently my lab demonstrated that regulation by lin-4 and let-7 in C. elegans also results in degradation of their mRNA targets. Currently, we are exploring the generality of mRNA degradation as an outcome of regulation by miRNAs. We are also attempting to identify the mRNA degradation intermediates and the protein factors that participate in this mechanism of regulation by miRNAs. Studying miRNAs and their targets in C. elegans allows us to analyze the effect of authentic mutants in miRNA genes on endogenous gene expression. By elucidating the function of miRNAs in this organism, we hope to contribute to the general understanding of this newly discovered and widely conserved mode of gene regulation.